Navegando por Palavras-chave "Structure-Activity Study"

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    Estudo de estrutura-atividade do peptídeo antimicrobiano IsCT1
    (Universidade Federal de São Paulo (UNIFESP), 2020-04-30) Oliveira, Cyntia Silva De [UNIFESP]; Oliveira Junior, Vani Xavier De [UNIFESP]; Universidade Federal de São Paulo
    Introduction: The increase in multidrug-resistant bacteria represents a major global health challenge, in this scenario, antimicrobial peptides represents a promising alternative for the development of new drugs due to the broad spectrum or good selectivity. Among them, IsCT1 (ILGKIWEGIKSLF-NH2) obtained from the venom of the scorpion Opisthacanthus madagascariensis, has a potent antimicrobial activity, but high hemolytic activity in human erythrocytes. Objectives: To obtain peptides based on the general structure of IsCT1 with point substitutions of amino acid residues on the hydrophilic, hydrophobic or both faces, in order to verify how these changes and their consequent physicochemical changes reflect on the structure and biological activity. Methodology: The peptides were synthesized in solid phase by the Fmoc strategy, purified by liquid chromatography (HPLC), characterized by mass spectrometry (LCESI/MS). Conformational studies were carried out by circular dichroism (CD) in water and solutions of PBS, SDS, TFE. Hemolytic activity assays were performed using human erythrocytes and the antimicrobial activity was tested against strains of Grampositive and Gram-negative bacteria. Anticancer activity was tested in human breast cancer cells / MCF-7A, and cytotoxicity in human breast epithelial cells / MCF-10A. Results and discussion: The analogs showed a reduction in hemolytic activity, mainly when made substitution of the glutamic acid residue present in position 8 of the IsCT1 peptide, this analogs also showed antimicrobial activity in low concentrations and high therapeutic indexes, except for the analogue An5, which had its load increased to +6 by the insertion of three lysine residues in addition to proline in position 8, its showed a reduction in antimicrobial activity and high hemolytic activity. In turn, An2 showed the best results of antimicrobial activity and absence of hemolytic activity up to the concentration of 128 μmol L-1 . It was also observed the activity against human breast cancer cells presented by IsCT1 and by two of the analogs synthesized with substitution in position 7, adding the proline residue (An2 and An8). A direct relationship between secondary structure and biological activity has not been established, since the analogs showed little tendency to form helix in TFE and varying values in SDS. The peptides were also tested for stability against enzymatic degradation, where an increase in resistance was observed, promoted by the insertion of proline in position 8 and a reduction in resistance, when proline was inserted in position 7. Conclusion: The results obtained show how the modifications of amino acid residues along the peptide sequence promote physical-chemical changes capable of interfering both in biological activity and in peptide stability.